Cyclooxygenase-2 Induced Pancreatic Cancer

环氧合酶 2 诱发胰腺癌

• 批准号: 8212143
• 负责人: SUSAN M FISCHER
• 金额: $ 31万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212143
• 关键词: Adenocarcinoma; Adenylate Cyclase; Age-Months; Animal Disease Models; Animal Model; Automobile Driving; Binding; CREB1 gene; Calcium; Cells; Characteristics; Chemoprevention; Chronic; Coxibs; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclin D1; Data; Development; Dinoprostone; Disease; Dominant-Negative Mutation; Epidermal Growth Factor Receptor; Etiology; Future; GTP-Binding Proteins; Genes; Health; Human; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inositol; Investigation; Lesion; Leukocytes; Link; Lymphocyte; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Metaplasia; Metaplastic; Molecular; Mus; Neoplastic Processes; PTGS2 gene; Pancreas; Pancreatic Adenocarcinoma; Pancreatitis; Pathway interactions; Phenotype; Phosphorylation; Play; Prevention; Prostaglandins; Protein Kinase C; Receptor Activation; Recruitment Activity; Research; Role; SRC gene; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Small Interfering RNA; Therapeutic; Tissues; Transgenic Mice; Up-Regulation; Vascular Endothelial Growth Factors; Work; celecoxib; chronic pancreatitis; cyclooxygenase 2; cytokine; human WFDC2 protein; human disease; inhibitor/antagonist; keratin 5; macrophage; neoplastic; pancreatic neoplasm; prevent; promoter; receptor; response; transcription factor; tumor; tumorigenic

DESCRIPTION (provided by applicant): Investigations into the role of cyclooxygenase-2 (COX-2) in pancreatitis and pancreatic cancer have been very limited. A recently generated transgenic mouse that over- expresses COX-2 under the control of a keratin 5 promoter, K5.COX-2, develops spontaneous pancreatitis leading to pancreatic adenocarcinoma that has many of the same histological and molecular characteristics as the human disease. This occurs with a 100% incidence and is fatal by 8 months of age. The major prostaglandin (PG) product, PGE2, binds to one or more of the 4 EP receptors. EP2 and EP4 are linked to adenylate cyclase causing an increase in cAMP and subsequent activation of protein kinase A (PKA) and phosphorylation of CREB. Preliminary data indicate that the cAMP/PKA/pCREB pathway is highly activated in pre-lesion pancreata of K5.COX-2 mice, however, the MAPK/Akt/NFkB pathway is also highly activated. We hypothesize that activation of both the cAMP/PKA/pCREB and MAPK/Akt/NFkB signaling pathways are required for a full neoplastic response as is the inflammatory response, and that inflammation is driving the metaplastic and neoplastic changes. Aim 1 will determine the requirement for PG signaling through the cAMP/PKA/pCREB pathway for adenocarcinoma development by generating transgenic mice with inducible, targeted activated CREB on a wildtype background, and dominant negative (dn)CREB on the K5.COX-2 background. Aim 2 will determine the critical involvement of MAPK/Akt/NFkB signaling in adenocarcinoma development through the use dnAkt/K5.COX-2 bitransgenic mice and the use of MAPK and NFkB inhibitors. Activation of c-Src, EGF receptors, Erk, Akt and NFkB will be assessed in wild type, pre-lesion and lesions from K5.COX-2 pancreata. Aim 3 will determine whether prostaglandins are driving acinar metaplasia by elevating cytokines that then recruit leukocytes. The effect of inhibition of COX-2 with celecoxib, or of inhibiting cytokine synthesis with pentoxyfylline, on cytokine expression, inflammatory cell infiltration and the development of acinar metaplasia and pancreatic cancer will be assessed. The effect of inhibition of COX-2 or cytokine synthesis on inflammatory cell infiltration in established lesions will also be determined to assess whether this will prevent further progression or reversion of the disease. PUBLIC HEALTH RELEVANCE: The proposed studies are significant because pancreatic cancer is one of the most fatal of all human malignancies and the lack of good animal models has severely hampered research into its etiology, prevention and treatment. Because of the associations between chronic inflammation, COX-2 and human pancreatic cancer, it is likely that the proposed work will generate information on the signaling pathways and receptors that are critical determinants in pancreatic cancer development, which should be useful for guiding future studies on chemoprevention and therapy.

描述（由申请人提供）：关于环氧合酶-2（考克斯-2）在胰腺炎和胰腺癌中作用的研究非常有限。最近产生的在角蛋白5启动子K5.考克斯-2的控制下过表达考克斯-2的转基因小鼠发生自发性胰腺炎，导致胰腺癌，其具有许多与人类疾病相同的组织学和分子特征。这种情况的发生率为100%，在8个月龄时是致命的。主要的前列腺素（PG）产物PGE 2与4种EP受体中的一种或多种结合。EP 2和EP 4与腺苷酸环化酶连接，导致cAMP增加，随后激活蛋白激酶A（PKA）和CREB磷酸化。初步数据表明，cAMP/PKA/pCREB通路在K5.COX-2小鼠的损伤前胰腺中高度活化，然而，MAPK/Akt/NFkB通路也高度活化。我们假设cAMP/PKA/pCREB和MAPK/Akt/NFkB信号通路的激活是完全肿瘤反应所需的，炎症反应也是如此，并且炎症驱动了化生和肿瘤变化。目的1将通过在野生型背景下产生具有可诱导的靶向活化CREB和在K5.COX-2背景下具有显性阴性（dn）CREB的转基因小鼠，确定通过cAMP/PKA/pCREB途径的PG信号传导对于腺癌发展的需要。目的2通过使用dnAkt/K5.COX-2双转基因小鼠和使用MAPK和NFkB抑制剂来确定MAPK/Akt/NFkB信号传导在腺癌发展中的关键参与。将在野生型、损伤前和来自K5.COX-2胰腺的损伤中评估c-Src、EGF受体、Erk、Akt和NFkB的活化。目的3将确定是否是通过提高细胞因子，然后招募白细胞来驱动腺泡化生。将评估用塞来昔布抑制考克斯-2或用戊氧基茶碱抑制细胞因子合成对细胞因子表达、炎性细胞浸润以及腺泡化生和胰腺癌发展的影响。还将确定抑制考克斯-2或细胞因子合成对已建立的病变中炎性细胞浸润的影响，以评估这是否将防止疾病的进一步进展或逆转。公共卫生关系：拟议的研究是重要的，因为胰腺癌是所有人类恶性肿瘤中最致命的一种，缺乏良好的动物模型严重阻碍了对其病因，预防和治疗的研究。由于慢性炎症，考克斯-2和人类胰腺癌之间的关联，它是可能的，拟议的工作将产生信息的信号通路和受体，是胰腺癌发展的关键决定因素，这应该是有用的，指导未来的化学预防和治疗的研究。